Endothelial adhesion molecules facilitate the entry of leukocytes into inflamed tissues. This in turn promotes neovascularization, a process central to the progression of rheumatoid arthritis, tumor growth and wound repair. Here we test the hypothesis that soluble endothelial adhesion molecules promote angiogenesis. Human recombinant soluble E-selectin and soluble vascular cell adhesion molecule-1 induced chemotaxis of human endothelial cells in vitro and were angiogenic in rat cornea. Soluble E-selectin acted on endothelial cells in part through a sialyl Lewis-X-dependent mechanism, while soluble vascular cell adhesion molecule-1 acted on endothelial cells in part through a very late antigen (VLA)-4 dependent mechanism. The chemotactic activity of rheumatoid synovial fluid for endothelial cells, and also its angiogenic activity, were blocked by antibodies to either soluble E-selectin or soluble vascular cell adhesion molecule-1. These results suggest a novel function for soluble endothelial adhesion molecules as mediators of angiogenesis.

Objective. Angiogenesis is an integral component of the vasculoproliferative phase of rheumatoid arthritis (RA). Recently, a heparin‐binding cytokine termed hepatocyte growth factor (HGF), or scatter factor (due to its ability to disperse cohesive epithelial colonies), was described. We conducted this study to investigate the hypothesis that this cytokine was present in the milieu of the inflamed joint, and that it contributed to the chemotaxis of endothelial cells in the synovial tissue. Methods. We examined synovial fluid, synovial tissue, and peripheral blood from 91 patients with RA and other arthritides. We used 83 total samples in an enzyme‐linked immunosorbent assay to quantitate the HGF in synovial fluids and peripheral blood. To determine whether the HGF was biologically active, an epithelial scatter factor assay was performed. Immunohistochemical analysis was used to determine localization in synovial tissues. To define a function for synovial HGF, we preincubated rheumatoid synovial fluids with neutralizing anti‐HGF and measured the ability of these synovial fluids to induce endothelial chemotaxis. Results. Synovial fluid from patients with RA contained a mean ± SEM HGF concentration of 2.0 ± 0.3 ng/ml, while synovial fluid from patients with other arthritides (including inflammatory arthritis) contained 2.4 ± 0.7 ng/ml HGF. Osteoarthritis (OA) patient samples contained the smallest quantities of synovial fluid HGF at 0.9 ± 0.1 ng/ml. RA synovial fluid contained significantly more HGF than did RA peripheral blood (1.1 ± 0.2 ng/ml) (P < 0.05). Rheumatoid synovial fluids induced more scattering of cells than did OA synovial fluids, suggesting a role for this cytokine in rheumatoid joint destruction. Interleukin‐1β induced expression of rheumatoid synovial tissue fibroblast antigenic HGF and scatter factor activity. Immunohistochemically, HGF, as well as the HGF receptor (the met gene product), localized to significantly more rheumatoid synovial tissue lining cells than normal lining cells (P < 0.05). Both HGF and its receptor immunolocalized to subsynovial macrophages as well. Levels of synovial tissue immunoreactive HGF correlated positively with the number of synovial tissue blood vessels. Anti‐HGF neutralized a mean of 24% of the chemotactic activity for endothelial cells found in 10 rheumatoid synovial fluid samples. Conclusion. These results indicate that synovial HGF may contribute to the vasculoproliferative phase of inflammatory arthritides such as RA, by inducing HGF‐mediated synovial neovascularization. These findings point to a newly described role for HGF in the fibroproliferative phase of RA‐associated synovitis.

Immunological mechanisms play an important role in the pathogenesis of atherosclerosis and atherosclerotic abdominal aortic aneurysms (AAA). Inflammatory leukocytes invade the vessel wall and produce cytokines which perpetuate the immune events underlying these diseases. Interleukin (IL)-1 beta, IL-8, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1, among others, may play a role in the generation by AAA. The aim of this study was to investigate the possible pathogenetic role of other proinflammatory cytokines, namely IL-2, IL-4, IL-6, and interferon (IFN)-gamma. Enzyme-linked immunosorbent assay of human explant culture supernatants revealed a significant increase in IFN-gamma production by AAA compared to occlusive (atherosclerotic) or normal (NL) aortic explants. IL-6 production was also increased in AAA compared to NL aortic explant supernatants. Neither AAA nor NL aortic tissues produced IL-2 or IL-4 in the same culture system. These results suggest that IL-6, a cytokine involved in T and B lymphocyte activation during inflammation, and IFN-gamma, which stimulates T and B lymphocytes, macrophages, endothelial cells and fibroblasts, may play a role in the pathogenesis of various vascular inflammatory diseases such as AAA.

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